Cutaneous T-cell lymphoma (CTCL) is a clonally-derived, skin-invasive malignancy of CD4+ T-lymphocytes with the phenotype of mature helper T-cells. Patients with advanced forms of CTCL characterized by rnultiple tumors or peripheral blood involvement typically have a poor prognosis. Our previous work has demonstrated that advanced CTCL is characterized by prominent immunologic defects including depressed cell-mediated immunity. A marked defect in IL-12 production in CTCL has also been noted, which may play a role in depressed cell-mediated immunity. Because evidence exists for an antitumor T-cell response and since IL-12 is pivotal in stimulating cytotoxic T-cells, several clinical trials have been performed with recombinant IL- 12 with 10 of 23 evaluable patients responding. Key observations in these small studies were 1) responses were rapid but were often eventually associated with an IL-12 refractory state, 2) the latter may be associated with downmodulation of IL-12 receptors on lymphocytes, 3) regressing lesions were intensely infiltrated with cytotoxic T-cells, and 4) more robust responses appeared to occur at the lower dose of 100 ng/kg used in the phase I trial. This proposal plans to study the in vivo effects of IL-12 in a newly initiated multicenter trial which will combine IL- 12 with escalating doses of IL-2. We propose to investigate the in vivo mechanisms of action of IL-12 by studying 1) skin infiltrating immune cells, 2) cytokine production in situ in skin lesions, and 3) extent of apoptosis within active skin lesions prior to and during IL-12 therapy and correlate this with lesion regression. We will also examine IL-12 responsive NK cell activity and interferon gamma production in concert with IL- 12 receptor expression and IL- 12 signal transduction prior to and prospectively during therapy to determine if downmodulation of receptors or alteration of Jak-Stat pathways accounts for tolerance to the clinical effects of IL-12. A more precise understanding of the effects of IL-12 will lead to the optimal use of this cytokine for this IL-12 responsive disease.